MutS-1
Encyclopedia
Mismatch repair
contributes to the overall fidelity of DNA replication
and is essential for combating the adverse effects
of damage to the genome
. It involves the correction of mismatched base pairs that have been missed by the proofreading
element of the DNA polymerase
complex
. The post-replicative Mismatch Repair System (MMRS) of Escherichia coli involves MutS (Mutator S), MutL and MutH proteins, and acts to correct point mutation
s or small insertion/deletion loops produced during DNA replication. MutS and MutL are involved in preventing recombination
between partially homologous
DNA sequence
s. The assembly of MMRS is initiated by MutS, which recognises and binds to mispaired nucleotide
s and allows further action of MutL and MutH to eliminate a portion of newly synthesized DNA strand containing the mispaired base
. MutS can also collaborate with methyltransferase
s in the repair of O(6)-methylguanine damage, which would otherwise pair with thymine during replication to create an O(6)mG:T mismatch. MutS exists as a dimer, where the two monomer
s have different conformations and form a heterodimer at the structural
level. Only one monomer recognises the mismatch specifically and has ADP bound. Non-specific major groove DNA-binding domains
from both monomers embrace the DNA in a clamp-like structure
. Mismatch binding
induces
ATP uptake and a conformational change
in the MutS protein, resulting in a clamp that translocates
on DNA.
MutS is a modular protein
with a complex
structure
, and is composed of:
Homologues
of MutS have been found in many species
including eukaryotes (MSH 1, 2, 3, 4, 5, and 6 proteins), archaea
and bacteria, and together these protein
s have been grouped into the MutS family. Although many of these proteins have similar activities to the E. coli MutS, there is significant diversity of function among the MutS family members. This diversity is even seen within species, where many species encode multiple MutS homologues
with distinct functions. Inter-species homologue
s may have arisen through frequent ancient horizontal gene transfer
of MutS (and MutL) from bacteria
to archaea and eukaryote
s via endosymbiotic ancestors of mitochondria and chloroplast
s.
This entry represents the N-terminal domain of proteins in the MutS family of DNA mismatch repair proteins, as well as closely related proteins. The N-terminal domain of MutS is responsible for mismatch recognition and forms a 6-stranded mixed beta-sheet surrounded by three alpha-helices, which is similar to the structure
of tRNA endonuclease. Yeast
MSH3, bacteria
l proteins involved in DNA mismatch repair, and the predicted protein product
of the Rep-3 gene of mouse share extensive sequence
similarity. Human MSH has been implicated in non-polyposis colorectal carcinoma
(HNPCC) and is a mismatch binding protein.
DNA mismatch repair
DNA mismatch repair is a system for recognizing and repairing erroneous insertion, deletion and mis-incorporation of bases that can arise during DNA replication and recombination, as well as repairing some forms of DNA damage....
contributes to the overall fidelity of DNA replication
DNA replication
DNA replication is a biological process that occurs in all living organisms and copies their DNA; it is the basis for biological inheritance. The process starts with one double-stranded DNA molecule and produces two identical copies of the molecule...
and is essential for combating the adverse effects
Adverse effect (medicine)
In medicine, an adverse effect is a harmful and undesired effect resulting from a medication or other intervention such as surgery.An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. If it results from an unsuitable or incorrect dosage or...
of damage to the genome
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
. It involves the correction of mismatched base pairs that have been missed by the proofreading
Proofreading (biology)
The term proofreading is used in genetics to refer to the error-correcting processes, first proposed by John Hopfield and Jacques Ninio, involved in DNA replication, immune system specificity, enzyme-substrate recognition among many other processes that require enhanced specificity...
element of the DNA polymerase
Polymerase
A polymerase is an enzyme whose central function is associated with polymers of nucleic acids such as RNA and DNA.The primary function of a polymerase is the polymerization of new DNA or RNA against an existing DNA or RNA template in the processes of replication and transcription...
complex
Protein complex
A multiprotein complex is a group of two or more associated polypeptide chains. If the different polypeptide chains contain different protein domain, the resulting multiprotein complex can have multiple catalytic functions...
. The post-replicative Mismatch Repair System (MMRS) of Escherichia coli involves MutS (Mutator S), MutL and MutH proteins, and acts to correct point mutation
Point mutation
A point mutation, or single base substitution, is a type of mutation that causes the replacement of a single base nucleotide with another nucleotide of the genetic material, DNA or RNA. Often the term point mutation also includes insertions or deletions of a single base pair...
s or small insertion/deletion loops produced during DNA replication. MutS and MutL are involved in preventing recombination
Recombination
Recombination may refer to:* Recombination , the process by which genetic material is broken and joined to other genetic material* Recombination , in semiconductors, the elimination of mobile charge carriers...
between partially homologous
Homology (biology)
Homology forms the basis of organization for comparative biology. In 1843, Richard Owen defined homology as "the same organ in different animals under every variety of form and function". Organs as different as a bat's wing, a seal's flipper, a cat's paw and a human hand have a common underlying...
DNA sequence
Sequence (biology)
A sequence in biology is the one-dimensional ordering of monomers, covalently linked within in a biopolymer; it is also referred to as the primary structure of the biological macromolecule.-See also:* Protein sequence* DNA sequence...
s. The assembly of MMRS is initiated by MutS, which recognises and binds to mispaired nucleotide
Nucleotide
Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides participate in cellular signaling , and are incorporated into important cofactors of enzymatic reactions...
s and allows further action of MutL and MutH to eliminate a portion of newly synthesized DNA strand containing the mispaired base
Base (chemistry)
For the term in genetics, see base A base in chemistry is a substance that can accept hydrogen ions or more generally, donate electron pairs. A soluble base is referred to as an alkali if it contains and releases hydroxide ions quantitatively...
. MutS can also collaborate with methyltransferase
Methyltransferase
A methyltransferase is a type of transferase enzyme that transfers a methyl group from a donor to an acceptor.Methylation often occurs on nucleic bases in DNA or amino acids in protein structures...
s in the repair of O(6)-methylguanine damage, which would otherwise pair with thymine during replication to create an O(6)mG:T mismatch. MutS exists as a dimer, where the two monomer
Monomer
A monomer is an atom or a small molecule that may bind chemically to other monomers to form a polymer; the term "monomeric protein" may also be used to describe one of the proteins making up a multiprotein complex...
s have different conformations and form a heterodimer at the structural
Secondary structure
In biochemistry and structural biology, secondary structure is the general three-dimensional form of local segments of biopolymers such as proteins and nucleic acids...
level. Only one monomer recognises the mismatch specifically and has ADP bound. Non-specific major groove DNA-binding domains
Protein domain
A protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...
from both monomers embrace the DNA in a clamp-like structure
Secondary structure
In biochemistry and structural biology, secondary structure is the general three-dimensional form of local segments of biopolymers such as proteins and nucleic acids...
. Mismatch binding
Binding (molecular)
Molecular binding is an attractive interaction between two molecules which results in a stable association in which the molecules are in close proximity to each other...
induces
Regulation of gene expression
Gene modulation redirects here. For information on therapeutic regulation of gene expression, see therapeutic gene modulation.Regulation of gene expression includes the processes that cells and viruses use to regulate the way that the information in genes is turned into gene products...
ATP uptake and a conformational change
Conformational change
A macromolecule is usually flexible and dynamic. It can change its shape in response to changes in its environment or other factors; each possible shape is called a conformation, and a transition between them is called a conformational change...
in the MutS protein, resulting in a clamp that translocates
Protein targeting
Protein targeting or protein sorting is the mechanism by which a cell transports proteins to the appropriate positions in the cell or outside of it. Sorting targets can be the inner space of an organelle, any of several interior membranes, the cell's outer membrane, or its exterior via secretion...
on DNA.
MutS is a modular protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
with a complex
Complex (chemistry)
In chemistry, a coordination complex or metal complex, is an atom or ion , bonded to a surrounding array of molecules or anions, that are in turn known as ligands or complexing agents...
structure
Cis-regulatory element
A cis-regulatory element or cis-element is a region of DNA or RNA that regulates the expression of genes located on that same molecule of DNA . This term is constructed from the Latin word cis, which means "on the same side as". These cis-regulatory elements are often binding sites for one or...
, and is composed of:
- N-terminal mismatch-recognition domain, which is similar in structureProtein structureProteins are an important class of biological macromolecules present in all organisms. Proteins are polymers of amino acids. Classified by their physical size, proteins are nanoparticles . Each protein polymer – also known as a polypeptide – consists of a sequence formed from 20 possible L-α-amino...
to tRNA endonucleaseEndonucleaseEndonucleases are enzymes that cleave the phosphodiester bond within a polynucleotide chain, in contrast to exonucleases, which cleave phosphodiester bonds at the end of a polynucleotide chain. Typically, a restriction site will be a palindromic sequence four to six nucleotides long. Most...
.
- Connector domain, which is similar in structureRNA structureBiomolecular structure is the structure of biomolecules, mainly proteins and the nucleic acids DNA and RNA. The structure of these molecules is frequently decomposed into primary structure, secondary structure, tertiary structure, and quaternary structure. The scaffold for this structure is...
to Holliday junction resolvase ruvC.
- Core domain, which is composed of two separate subdomains that join together to form a helical bundle; from within the core domain, two helicesAlpha helixA common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...
act as levers that extend towards (but do not touch) the DNA.
- Clamp domain, which is inserted between the two subdomains of the core domainDomain (biology)In biological taxonomy, a domain is the highest taxonomic rank of organisms, higher than a kingdom. According to the three-domain system of Carl Woese, introduced in 1990, the Tree of Life consists of three domains: Archaea, Bacteria and Eukarya...
at the top of the lever helices; the clamp domain has a beta-sheet structureTertiary structureIn biochemistry and molecular biology, the tertiary structure of a protein or any other macromolecule is its three-dimensional structure, as defined by the atomic coordinates.-Relationship to primary structure:...
.
- ATPase domain (connected to the core domain), which has a classical Walker A motif.
- HTH (helix-turn-helix) domain, which is involved in dimerProtein dimerIn biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...
contacts.
Homologues
Homology (biology)
Homology forms the basis of organization for comparative biology. In 1843, Richard Owen defined homology as "the same organ in different animals under every variety of form and function". Organs as different as a bat's wing, a seal's flipper, a cat's paw and a human hand have a common underlying...
of MutS have been found in many species
Species
In biology, a species is one of the basic units of biological classification and a taxonomic rank. A species is often defined as a group of organisms capable of interbreeding and producing fertile offspring. While in many cases this definition is adequate, more precise or differing measures are...
including eukaryotes (MSH 1, 2, 3, 4, 5, and 6 proteins), archaea
Archaea
The Archaea are a group of single-celled microorganisms. A single individual or species from this domain is called an archaeon...
and bacteria, and together these protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s have been grouped into the MutS family. Although many of these proteins have similar activities to the E. coli MutS, there is significant diversity of function among the MutS family members. This diversity is even seen within species, where many species encode multiple MutS homologues
Homology (biology)
Homology forms the basis of organization for comparative biology. In 1843, Richard Owen defined homology as "the same organ in different animals under every variety of form and function". Organs as different as a bat's wing, a seal's flipper, a cat's paw and a human hand have a common underlying...
with distinct functions. Inter-species homologue
Homology (biology)
Homology forms the basis of organization for comparative biology. In 1843, Richard Owen defined homology as "the same organ in different animals under every variety of form and function". Organs as different as a bat's wing, a seal's flipper, a cat's paw and a human hand have a common underlying...
s may have arisen through frequent ancient horizontal gene transfer
Horizontal gene transfer
Horizontal gene transfer , also lateral gene transfer , is any process in which an organism incorporates genetic material from another organism without being the offspring of that organism...
of MutS (and MutL) from bacteria
Zinc dependent phospholipase C
Zinc-dependent prokaryotic phospholipases C is a family of bacterial phospholipases C, some of which are also known as alpha toxins.Bacillus cereus contains a monomeric phospholipase C of 245 amino-acid residues. Although PLC prefers to acton phosphatidylcholine, it also shows weak catalytic...
to archaea and eukaryote
Eukaryote
A eukaryote is an organism whose cells contain complex structures enclosed within membranes. Eukaryotes may more formally be referred to as the taxon Eukarya or Eukaryota. The defining membrane-bound structure that sets eukaryotic cells apart from prokaryotic cells is the nucleus, or nuclear...
s via endosymbiotic ancestors of mitochondria and chloroplast
Chloroplast
Chloroplasts are organelles found in plant cells and other eukaryotic organisms that conduct photosynthesis. Chloroplasts capture light energy to conserve free energy in the form of ATP and reduce NADP to NADPH through a complex set of processes called photosynthesis.Chloroplasts are green...
s.
This entry represents the N-terminal domain of proteins in the MutS family of DNA mismatch repair proteins, as well as closely related proteins. The N-terminal domain of MutS is responsible for mismatch recognition and forms a 6-stranded mixed beta-sheet surrounded by three alpha-helices, which is similar to the structure
Structure
Structure is a fundamental, tangible or intangible notion referring to the recognition, observation, nature, and permanence of patterns and relationships of entities. This notion may itself be an object, such as a built structure, or an attribute, such as the structure of society...
of tRNA endonuclease. Yeast
Saccharomyces cerevisiae
Saccharomyces cerevisiae is a species of yeast. It is perhaps the most useful yeast, having been instrumental to baking and brewing since ancient times. It is believed that it was originally isolated from the skin of grapes...
MSH3, bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
l proteins involved in DNA mismatch repair, and the predicted protein product
Product (chemistry)
Product are formed during chemical reactions as reagents are consumed. Products have lower energy than the reagents and are produced during the reaction according to the second law of thermodynamics. The released energy comes from changes in chemical bonds between atoms in reagent molecules and...
of the Rep-3 gene of mouse share extensive sequence
Sequence
In mathematics, a sequence is an ordered list of objects . Like a set, it contains members , and the number of terms is called the length of the sequence. Unlike a set, order matters, and exactly the same elements can appear multiple times at different positions in the sequence...
similarity. Human MSH has been implicated in non-polyposis colorectal carcinoma
Carcinoma
Carcinoma is the medical term for the most common type of cancer occurring in humans. Put simply, a carcinoma is a cancer that begins in a tissue that lines the inner or outer surfaces of the body, and that generally arises from cells originating in the endodermal or ectodermal germ layer during...
(HNPCC) and is a mismatch binding protein.